Islet Transplantation in Patients with Type 1 Diabetes Mellitus

Summary

Evidence Report/Technology Assessment: Number 98

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Under its Evidence-based Practice Program, the Agency for Healthcare Research and Quality (AHRQ) is developing scientific information for other agencies and organizations on which to base clinical guidelines, performance measures, and other quality improvement tools. Contractor institutions review all relevant scientific literature on assigned clinical care topics and produce evidence reports and technology assessments, conduct research on methodologies and the effectiveness of their implementation, and participate in technical assistance activities.

Introduction

Pancreatic islets are small clusters of endocrine
cells in the pancreas that include insulin-producing
beta cells. In type 1 diabetes—also
known as juvenile or insulin-dependent
diabetes—the body's immune system specifically
destroys the beta cells, resulting in a loss of insulin
production. Pancreas transplants have been used
as a way to restore insulin production, but require
long-term treatment to prevent immune rejection
of the transplanted organ. Islet transplantation
offers a potential alternative to whole-organ
pancreas transplantation, but early attempts rarely
succeeded.

Following the introduction of the
Edmonton transplant protocol in 1999,
developed at the University of Alberta in Canada,
major islet transplant centers have developed and
refined new procedures, are enlisting patients into
clinical studies and following their progress, and
are reporting detailed data to a new transplant
registry.

This report represents the current state of
the evidence in a field where clinical research is
actively progressing.

Whole-organ pancreas transplants were initially
performed in patients with type 1 diabetes who
were undergoing kidney transplants (for kidney
failure), with the pancreas transplanted either at
the same time as the kidney or in a later
operation. Compared with patients receiving
only a cadaver kidney transplant, patients
receiving a simultaneous pancreas-kidney
transplant have improved long term survival—although immediately after surgery, during the
early post-transplant period, survival is worse.1-3
Transplant of a pancreas together with a kidney
also has positive effects on low blood
sugar/hypoglycemia,4,5 kidney complications,6,7 and high blood pressure/hypertension.8

Over the past decade, pancreas transplant alone
(PTA) has been used selectively in some type 1
diabetes patients. Patients considered for this
approach are those for whom the potential benefit
of the procedure is expected to offset the adverse
consequences of lifelong immunosuppressive
therapy, which keeps their immune system from
rejecting the transplanted organ. PTA is
recommended only for patients with a history of
frequent and severe metabolic complications,
severe and incapacitating clinical and emotional
problems with receiving insulin shots, or
consistent failure of insulin-based management to
prevent acute complications.9

The results of the Diabetes Control and Complications Trial
(DCCT) demonstrate that intensive insulin
therapy significantly improves control of blood
sugar (glucose) levels and reduces the risk of
secondary complications, such as eye problems,
nerve damage, kidney damage, and cardiovascular
disease.10
However, there is a small population of
patients with unstable type 1 diabetes who,
nevertheless, have difficulty maintaining glucose
control with administration of insulin injections.
Some of these patients develop severe
hypoglycemia without the usual associated
warning signs.11 Untreated, severe hypoglycemic
episodes may result in coma, seizures, and death.
Such patients may require constant supervision by
a family member or caretaker.

Following the
introduction of the Edmonton protocol, islet
transplantation has largely been used in patients
who are candidates for PTA; most have been
selected due to their severe and frequent
hypoglycemic episodes.

Transplanted islets are infused into the portal
vein through a catheter and lodge in the liver.
Because islet transplantation does not require a
large abdominal incision, it is a less-invasive
alternative to whole-organ transplantation and
avoids the unhealthy side-effects of complex
surgery. However, early protocols resulted in only
around 10 percent of patients achieving insulin
independence at 1 year after the procedure.
Nevertheless, interest in this approach remained high due to improvement in long-term diabetic consequences in studies of islet-transplanted animals and in those patients
undergoing islet transplant who were able to maintain insulin
independence. For example, in the pre-Edmonton era, one
center reported reduced cardiovascular mortality and kidney
damage in their few patients with long-term, successfully
transplanted islets.12

Improved results for insulin independence and maintenance
of normal blood glucose levels have been achieved with newer
protocols that use a low-dose immunosuppressive therapy
without glucocorticoid drugs, improved islet preparation, and
infuse a minimum islet mass of 9,000 islet-equivalents per
kilogram (IEq/kg) of body weight. The first of these protocols
was the Edmonton protocol;13 subsequent protocols have been
developed at other centers (e.g., Universities of Minnesota and
Miami).14,15

As interest in establishing new islet transplant
centers increases, institutional collaborations with established
preparation centers will play a large role due to the startup costs
for an islet preparation facility, regulatory issues, and
complexity of the isolation procedure.16 The Division
of Clinical Research at the National Institutes of Health's
National Center for Research Resources, supports 10 Islet Cell
Resource Centers in the U.S. These centers isolate, purify,
characterize, and distribute human pancreatic islets for
subsequent transplantation in approved clinical protocols (for
additional information, go to www.ncrr.nih.gov/clinical/cr_icr.asp).

Currently, a limitation on transplanting islets is that two or
more donor organs are usually required for successful
transplantation. The low availability of donor pancreas organs
limits the number of pancreas or islet transplants that can be
performed. For 2002, the Organ Procurement and
Transplantation Network reported 6,187 total deceased organ
donors, 1,870 pancreas organs recovered, and 1,461 pancreas
organs transplanted.17
A smaller, unreported number of
pancreas organs are also collected and preserved (harvested)
specifically for islet transplantation research.18
In contrast, a total of 9,691 individual kidneys were harvested and
transplanted from the same group of organ donors.

Islet preparations are subject to regulation by the U.S. Food
and Drug Administration (FDA) as biological products and as
drugs. Because the use of cells derived from whole organs
meets the criteria for a biologic product to be regulated under
the Public Health Service Act, the FDA classifies
transplantation of allogeneic (not genetically identical to the
recipient) islets as somatic cell therapy, which requires
premarket approval.19

Islets also meet the definition of a drug
under the Federal Food, Drug, and Cosmetic Act. Clinical
studies to determine the safety and effectiveness outcomes of
allogeneic islet transplantation must be conducted under FDA's
investigational new drug (IND) regulations. At least 35 IND
applications have been submitted to the FDA,19
but, as of this writing, no center has as yet submitted a biologics license
application.

Outcomes of interest to the authors of this evidence report
are early and long-term clinical diabetic outcomes, biologic
outcomes that are indicators of graft function and glycemic
(blood-sugar) control, and adverse outcomes. Early clinical
outcome measures are insulin independence, percent of prior
insulin use, hypoglycemic episodes, and quality of life. For
patients with type I diabetes, improvement in long-term
diabetic outcomes is the measure of ultimate success of islet
transplantation. The objective is to reduce or eliminate long-term
diabetic complications such as eye disease, nerve damage,
kidney damage, and cardiovascular disease. Measurement of C-peptide
and HbA1c (glycated hemoglobin) are biological
outcomes that are indicators of graft function and glycemic
control, respectively.

Potential adverse events of islet transplant
may be direct consequences of the procedure (for example,
hemorrhage or thrombosis from through-the-skin access to the
portal vein) or the continued immunosuppression needed to
maintain viability and function of the transplanted islets.
Adverse effects of immunosuppression may be near-term (such
as mouth ulceration, diarrhea, or anemia) or long-term
(including kidney disease, post-transplant cancers of the
immune system, other cancers, and cytomegalovirus or other
infections).

A consensus definition of successful islet transplantation was
proposed at a recent meeting of the FDA Biological Response
Modifiers Advisory Committee: restoration of sustained
euglycemia with no or a reduced exogenous insulin
requirement.20

Clinical outcome parameters that can be used to
measure success are insulin independence or percent of prior
insulin use, frequency and severity of hypoglycemic episodes,
and quality of life. However, in the absence of well-controlled
and well-reported studies, insulin independence is the most
persuasive measure available to establish the success of the
procedure.

The National Institute of Diabetes and Digestive and
Kidney Diseases (NIDDK) initiated and funded the
Collaborative Islet Transplant Registry (CITR) in September 2001. The CITR will develop and implement reporting standards, compile data on islet transplants in the U.S. and
Canada, and perform and communicate analyses of outcomes
(http://www.citregistry.org).
Unfortunately, the first CITR report was not yet available at
the time this evidence report was prepared. In the future, the
Registry will be the most comprehensive source of data on the
outcomes of islet transplant. While the CITR will provide
aggregated data on outcomes, published studies from individual
centers still remains the best source of detailed results and of
data on center-specific outcomes.

Methods

As much as possible, the protocol for this review was
designed prospectively to define:

Study objectives.

Search strategy.

Patient populations of interest.

Study selection criteria.

Outcomes of interest.

Data elements to be abstracted.

Methods for abstraction.

Methods for study quality assessment.

The report addresses the following four key questions:

What are the outcomes for selected diabetes patients treated with islet transplantation compared with similar patients who receive whole-organ pancreas transplants or medical (nontransplant) management of their disease? Are similar outcomes achievable outside of the investigational setting?

What criteria should be used to select patients for islet transplantation and what are the outcomes for relevant patient subgroups?

What are the incidence and severity of adverse effects associated with the islet transplantation procedure and with the immunosuppressive regimens? How do these compare with the adverse effects associated with whole-organ pancreas transplantation or medical management?

What is the evidence that the insulin independence or significantly reduced insulin dependence achieved with islet transplantation can be maintained long-term after the initial transplant, or with additional transplants in the event of failure of the original procedure? How often must successive transplants be performed?

This report is limited to transplantation of unaltered human
allogeneic islets harvested from donor organs. Thus, cultured
islets from donor organs are included, but the following are
excluded:

Autologous islets (from the patient's own pancreas).

Islets from pig pancreas.

Genetically altered islets.

Islets prepared from stem cells.

The MEDLINE® database was searched through October 2003 for recently published research articles and for relevant background information. Search was limited to articles with an
English-language abstract. Bibliographies of relevant articles
were also searched and the project's Technical Expert Panel was
queried for additional relevant articles. Registry data, recent
meeting abstracts, and presentations by investigators from key
research centers were also sought.

For all of the key questions, studies were included if they:

Reported prospective trials of islet transplantation.

Reported on outcomes of interest with at least 3 months of followup.

Used a transplant protocol based on the Edmonton protocol or a subsequently developed protocol designed to improve upon aspects of the procedure.

Were available as a full-length publication, abstract, or poster/slide presentation provided by the original presenter.

All abstracts initially retrieved by the search strategy were
reviewed by one researcher who also reviewed the full-text
articles to determine whether study selection criteria were met.
Selected papers were abstracted by a single reviewer and
evidence tables were fact-checked by a second reviewer. After
initial review of the evidence on islet transplantation, the
decision was made that it was premature to compare this
technique with whole-organ pancreas transplants; hence, a
systematic review of the evidence on pancreas transplant
outcomes was not undertaken for this report.

Results

Although more than 2,000 abstracts were reviewed, almost
all indexed clinical studies were completed prior to the
adoption of the Edmonton protocol. As a result, few articles
were retrieved and included in this review. Of the studies
relevant to the Edmonton protocol, only 12 published
articles13,14,16,21-29 reported efficacy and adverse outcomes, and
two additional articles30,31
reported only adverse outcomes.

Due to the scarcity of published articles, abstracts and
presentations from five scientific conferences were reviewed,
and those meeting the selection criteria were summarized as
supplementary sources that provide preliminary results of
studies anticipated to be fully reported in the next 2 years.
Because summary data from the CITR is not yet available, a
summary of results from transplant groups attending the 2002
Second Annual Annenberg Symposium, in Rancho Mirage,
CA, represents the only available effort to collate islet transplant
data from active centers and is also included in this report.

It was not possible to summarize and pool together the most
recent outcomes from each reporting center for several reasons:

First, some centers reported different outcomes on different numbers of patients in more than one publication, precluding an accurate synthesis.

Second, different centers reported the same type of outcome in different ways. Thus, a standardized data collection, such as that in progress by the CITR, will be needed for an accurate and complete data summary.

For these reasons, data in this report are generally presented by center.
Moreover, reports on the outcomes of islet transplantation from
a single center often combine results from patients treated on
different protocols. Protocol characteristics are noted in the
evidence tables for published reports, but this review makes no
attempt to compare the outcomes of different protocols.

Published data on the clinical outcomes of islet-only
transplantation are limited by small patient numbers, few
transplant centers, short duration of followup, and by lack of
standardized methods of reporting outcomes. Data are also
lacking on quality-of-life outcomes. Meeting abstracts and
presentations supplemented published reports with larger
numbers of patients and reporting transplant centers. Efforts
are ongoing to update and expand long-term transplant results
and quality-of-life data, disseminate protocols to additional
centers, and standardize reporting of outcomes. The available
evidence is summarized below:

Islet-alone transplantation has been used in a highly
selected population of type 1 diabetic patients who have
been selected for transplantation based on a history of
frequent and severe metabolic complications, severe and incapacitating clinical and emotional problems with exogenous insulin therapy, or consistent failure of insulin-based
management to prevent acute complications.

There are sufficient data to conclude that there is a high
rate of technical success for islet-alone transplantation.
Five centers published reports14,16,21,25,29
on 47 patients who completed a transplant protocol. Of these, patients 44 (94
percent) achieved insulin independence over the 3-month
post-transplant period.

Clinical outcomes from presently available data can be
summarized as follows:

Published data from three centers14,21,29 report that 28 of
37 patients (76 percent of those completing a transplant
protocol) maintained insulin independence for 1 year.
Four centers that followed 104 patients for at least 12
months report insulin independence in 50 to 90 percent
of patients in recent abstracts.

Only one published study (from the Edmonton group) 22
reported four of six patients remained insulin
independent after 2 years of followup. In one abstract
from Edmonton, 48 patients underwent transplantation
and 15 were followed for 2 or more years. Statistical
analysis estimated that the probability of remaining
insulin-independent at 2 years was 64 percent.

Two institutions published14,22
detailed information on 23 transplant patients who had at least 1 year of
followup. Of these, 19 (83 percent) had normal blood-sugar
levels without hypoglycemic episodes (were
euglycemic), and needed no or reduced amounts of
additional insulin.

All published series report that hypoglycemic episodes
were less frequent or intense in insulin-independent
transplant patients. In three series14,22,29 reporting on 26
patients who completed the transplant protocol,
hypoglycemic episodes were also reduced in nine
patients who exhibited continued C-peptide secretion,
but who were not insulin independent at 1 year.
Abstracts report this outcome less consistently but,
where reported, hypoglycemic episodes were eliminated
in insulin-independent patients.

In each published series14,16,22,25,26,29
and for all insulin-independent patients, mean HbA1c decreased from
greater than 7 percent to less than 6.5 percent; 7 percent
or less is recommended to avoid or delay progression of
diabetic complications. Where reported in meeting
abstracts, in most cases the mean HbA1c level after
transplantation was less than 6.5 percent; this level, was
maintained for up to 3 years post-transplant in two
series (13 patients reported on, total).

Data are scant on the effects of islet transplantation on
long-term diabetic consequences. In one publication,22
the Edmonton group reported on 17 subjects who completed
the transplant protocol. Damage to the retina progressed
in three patients and required laser photocoagulation
treatment. Nine patients either started or increased
treatment for high blood pressure. Cholesterol rose in 15
patients, of whom 11 required statin therapy. There were
no major changes in nerve damage. Serum creatinine and
urine protein levels only showed significant changes in two
patients with pre-existing kidney disease.

Infrequent but serious adverse events (such as portal vein
thrombosis or hemorrhage) have occurred in patients given
islet transplants, but it is not possible from present data to
estimate their frequency.14,21,29 Recent changes in the
transplant procedure reportedly minimize the risks of these
adverse events. No procedure-related deaths have been
reported among patients who received islets alone.
Notably, no publication or abstracts reported
cytomegalovirus infection in any patients given islet-only
transplants. Post-transplant immune system cancers also
have not been reported so far, but this may reflect the small
number of subjects studied.

The available evidence is insufficient to evaluate the long-term
consequences of immune system suppression, any
long-term effects of the islet graft, and the potential need
for and consequences of supplemental islet transplants.

The majority of transplants using the newer protocols have
been of islets alone. However, it has been reported
(mainly in meeting abstracts and presentations) that 30
islet transplants after or simultaneous with kidney
transplants have been attempted; in most cases, followup is
less than 1 year. The present evidence is insufficient to
permit conclusions for this type of transplant.

Discussion

The available evidence demonstrates the technical feasibility
and superior procedural success of islet transplantation using
the Edmonton and more recent protocols. Where 1-year
followup has been reported, most patients are insulin
independent and free of severe hypoglycemic episodes. At
present, 100 or more patients have been followed for 1 year
after transplantation, and the Edmonton group recently
reported on 15 patients followed for 2 years or more. Evidence
on longer-term outcomes or durability of the procedure is not
yet available. Therefore, it is not yet possible to assess the effects
on diabetic complications or the consequences of lifelong
immunosuppression.

Reports from the CITR are expected in the near future.
These will provide systematic data on outcomes of patients
treated at the major islet transplant centers, and will eventually
accumulate data on long-term outcomes. The CITR plans to
collect data on patient characteristics at transplantation (for
post-Edmonton protocols only, and including retrospective
data) as well as long-term followup data on the secondary
complications of diabetes. The addition of data on the
presence and severity of retinopathy, nerve damage, and other
diabetic complications in the patients prior to transplantation would aid the interpretation of long-term results. Randomized, controlled trials of islet transplantation (in direct comparison to
no treatment or whole-organ transplantation) do not exist and
are unlikely to be conducted. Thus, pre- and post-procedure
evaluations, which are likely to be the only source of evidence
to evaluate this procedure, should proceed with the utmost
rigor.

As is the case with many medical or surgical procedures,
outcomes may vary by center due to the transplant team's
experience or specifics of the treatment. Moreover, such
variation can be difficult to discover when the number of
procedures is too small to reach firm statistical conclusions.
Center-specific data will complement aggregate data in
evaluating the outcomes of islet transplants, setting standards
for performance, and improving outcomes.

Long-term followup will outline the durability of islet graft
function and the need for repeat procedures. Uncertainties
remain:

Should patients who fail to maintain insulin independence be administered additional islet transplants?

Does reactivation of autoimmune reactions against beta cells affect the success of subsequent transplants?

Do the risks of the procedure increase with successive transplants?

At present, the supply of donor pancreases stringently limits
the availability of islet transplants. However, refining the islet
isolation and transplant procedures could promote more
vigorous efforts at organ collection, and perhaps make islet
transplantation more available. Simultaneous transplant of
islets and kidneys is being attempted and may represent
another population of patients using islet transplantation.
Ongoing research on innovations in immunosuppression
regimens, and in techniques to prevent rejection or induce
tolerance of transplants, may eventually improve the benefit-to-risk
ratio of the procedure; methods of in vitro production may
also increase the availability of islets for transplantation. While
pancreas and islet transplantation are now the only means of
achieving physiologic insulin regulation, continuous glucose
monitoring and insulin infusion technologies are being
developed in hope of someday developing an artificial pancreas.
As innovations in the management of type I diabetes emerge,
risks and benefits, relative-effectiveness, and cost-effectiveness
for various patient populations should be carefully evaluated.

10. The Diabetes Control and Complications Trial Research Group. The
effect of intensive treatment of diabetes on the development and
progression of long term complications in insulin-dependent diabetes
mellitus. N Engl J Med 1993; 329:977-86.